Arthritis, or arthralgia, generally refers to inflammatory disorders of the joints of the body, and is usually accompanied by pain, swelling and stiffness. Arthritis may result from any of several causes including infections, trauma, degenerative disorders, metabolic disorders or disturbances or other unknown etiologies.
Rheumatoid Arthritis (RA), for example, is a chronic inflammatory disorder of the synovial membranes, and is one of the most common systemic autoimmune diseases. The diagnosis of RA depends primarily on clinical manifestations, but laboratory results are helpful in differential diagnosis and disease management. Early diagnosis of RA is important both in disease treatment and management. Kim and Weisman (2000) Arthritis. Rheum. 43:473-84.
The serum of affected patients contains factors that may be markers for the disease, allowing for early diagnosis. Historically, rheumatoid factor (RF) has long been one of the primary serologic indicators for RA. Additionally, anti-keratin autoantibodies (AKA), also known as anti-perinuclear autoantibodies, are detected in 40-55% of RA patients and in 40-50% of clinically diagnosed RA patients who are RF negative. Vincent et al. (1989) Ann. Rheum. Dis. 48:712-22; Corconnier et al. (1996) Br. J. Rheumatol. 35:620-4; Gabay et al. (1993) Ann. Rheum. Dis. 52:785-9. AKA is generally considered to be significantly more specific than RF. Additionally, AKA may precede the clinical appearance of RA by months or years. PCT Publication No. 2010102412 entitled “Compositions and Methods for Characterizing Arthritic Conditions” also describes autoantibodies to 14-3-3 proteins and methods of using them to evaluate arthritic conditions such as RA. For example, 14-3-3 eta is normally an intracellular protein and only in the disease state is it released into the extracellular space. As such, serum 14-3-3 eta and/or autoantibodies to same have diagnostic utility as markers that complement other serologic indicators in early and established RA and are associated with joint damage in RA and PsA,
Recently it was determined that AKA recognize an epitope that contains citrulline. von Venrooj (2000) Arthritis Res. 52:785-9. Citrullination is a form of a post-translational modification (PTM) whereby peptidylarginine deiminases (PAD) catalyze the deimination of the amino acid arginine (R) to citrulline (C) resulting in a chemical change liberating a nitrogen-based moiety. Disregulated citrullination appears to be an active process in inflammatory conditions like RA whereby an “insult” results in 1) activation of PAD; 2) release of PAD enzymes into the synovial space; 3) citrullination of extracellular proteins like vimentin and filaggrin; 4) a humoral immune response against the citrullinated antigens and 5) the perpetuation of the disease. Detection of these anti-citrullinated antibodies may also be useful in the early diagnosis of RA.
IgG antibodies against a synthetic peptide containing citrulline known as CCP (Cyclic Citrullinated Peptide) has proven to be better than either AKA or RF testing in differentiating RA from other autoimmune diseases, and the presence of anti-CCP antibody occurs independently of elevated RF levels in patients with RA. However, a significant percentage of patients are or remain seronegative for anti-CCP. Accordingly, there remains a significant need in the art for better and more specific diagnostic indicators of this disease.